tbuckley/cabot-search huggingface dataset:
Stress Keratin 17 Expression in Head and Neck Cancer Contributes to Immune Evasion and Resistance to Immune-Checkpoint Blockade
Authors: Wei Wang, Taja Lozar, Athena E. Golfinos, Denis Lee, Ellery Gronski, Ella Ward-Shaw, Mitchell Hayes, Justine Y. Bruce, Randall J. Kimple, Rong Hu, Paul M. Harari, Jin Xu, Aysenur Keske, Paul M. Sondel, Megan B. Fitzpatrick, Huy Q. Dinh, Paul F. Lambert
Journal: Clinical Cancer Research (2022)

Abstract Purpose: We investigated whether in human head and neck squamous cell carcinoma (HNSCC) high levels of expression of stress keratin 17 (K17) are associated with poor survival and resistance to immunotherapy. Experimental Design: We investigated the role of K17 in regulating both the tumor microenvironment and immune responsiveness of HNSCC using a syngeneic mouse HNSCC model, MOC2. MOC2 gives rise to immunologically cold tumors that are resistant to immune-checkpoint blockade (ICB). We engineered multiple, independent K17 knockout (KO) MOC2 cell lines and monitored their growth and response to ICB. We also measured K17 expression in human HNSCC of patients undergoing ICB. Results: MOC2 tumors were found to express K17 at high levels. When knocked out for K17 (K17KO MOC2), these cells formed tumors that grew slowly or spontaneously regressed and had a high CD8+ T-cell infiltrate in immunocompetent syngeneic C57BL/6 mice compared with parental MOC2 tumors. This phenotype was reversed when we depleted mice for T cells. Whereas parental MOC2 tumors were resistant to ICB treatment, K17KO MOC2 tumors that did not spontaneously regress were eliminated upon ICB treatment. In a cohort of patients with HNSCC receiving pembrolizumab, high K17 expression correlated with poor response. Single-cell RNA-sequencing analysis revealed broad differences in the immune landscape of K17KO MOC2 tumors compared with parental MOC2 tumors, including differences in multiple lymphoid and myeloid cell types. Conclusions: We demonstrate that K17 expression in HNSCC contributes to immune evasion and resistance to ICB treatment by broadly altering immune landscapes of tumors.
DIPG-26. Targeted Protein Degradation of LSD1 synergizes with HDAC inhibitors in Diffuse Intrinsic Pontine Glioma
Authors: Andrew Groves, Rebecca Poetschke, Hafsa Mire, Eshini Panditharatna, Maria Tarazona Guzman, Jun Qi, Mariella Filbin
Journal: Neuro-Oncology (2022)

Abstract Diffuse intrinsic pontine glioma (DIPG) remains one of the most lethal brain tumors in all of childhood with no effective treatments besides radiation, which only extends survival a few months. Against this backdrop, our lab recently executed a focused CRISPR negative selection screen in DIPG cell lines after treatment with the histone deacetylase (HDAC) inhibitor panobinostat and discovered a strong co-dependence with the histone demethylase LSD1. To further explore the therapeutic potential of this synergistic interaction, we tested a drug library of HDAC- and LSD1- targeting drugs with the goal of identifying a combination with optimal synergy and blood brain barrier (BBB) penetration suitable for clinical translation. We were surprised to find that traditional catalytic LSD1 inhibitors had minimal effect in isolation and did not seem to synergize with HDAC inhibitors, while a recently described CoREST/LSD1 degrader named UM171 phenocopied the effects seen in our CRISPR screen. Degraders are a class of compounds that recruit an E3 ubiquitin ligase to a protein-of-interest and cause target ubiquitination and proteasomal degradation. Given our unexpected finding, we hypothesized that UM171 induces synergy with HDAC inhibitors through elimination of a scaffolding function of LSD1. To prove this, we knocked out LSD1 using CRISPR/Cas9 and subsequently treated with a panel of HDAC inhibitors, which showed a signification sensitization of DIPG cells to HDAC inhibitors compared to standard controls. We also confirmed that UM171 interacts with the CoREST complex (members include LSD1, RCOR1, HDAC1/2) by performing streptavidin bead pull down with a newly synthesized biotin-conjugated UM171 probe. In summary, our results show that targeting LSD1 for degradation in combination with HDAC inhibition is a synergistic strategy in DIPG worthy of further translational study.
TWT-203: Phase 1b/2 dose-confirming study of CFI-402257 as a single agent in advanced solid tumors and in combination with fulvestrant in patients with ER+/HER2- advanced breast cancer after disease progression on prior CDK4/6 and endocrine therapy.
Authors: Robert Wesolowski, Mark R. Bray, Glenn C. Michelson, Emily L. Roberts-Thomson, Trisha Denny, David W. Cescon
Journal: Journal of Clinical Oncology (2022)

TPS1123 Background: TTK (Threonine Tyrosine Kinase also known as Monopolar spindle 1 [Mps1]), is a dual-specificity serine-threonine kinase critical for anaphase promoting complex/cyclosome inhibition at the spindle assembly checkpoint, and is required for chromosome alignment and error correction. Inhibition of TTK causes cells to prematurely exit mitosis with unattached chromosomes, resulting in aneuploidy and cell death. Higher TTK tumor levels correlate with worse prognosis and may contribute to the survival and proliferation of aneuploid cells. CFI-402257, a potent and selective inhibitor of TTK inhibits the growth of a variety of human cancer-derived cell lines with IC50 of 8-40 nM. A first-in-human phase 1 study of CFI-402257 administered orally as a single agent, demonstrated a tolerable safety profile and evidence of clinical activity in patients with advanced solid tumors. The MTD was 168 mg daily, and the study expanded to 3 cohorts: solid tumors, HER2-negative breast cancer, and hormone receptor positive (HR+/HER2-) breast cancer in combination with fulvestrant. The dose limiting toxicity was manageable and reversible dose-dependent neutropenia. Investigator-confirmed partial responses (cPR) were observed in 5 patients (10.6%) with 25 (53.2%) exhibiting disease control. In the HR+/HER2- breast cancer population previously treated with cyclin dependent kinase 4/6 inhibitors (CDK4/6i) and aromatase inhibitors, there were 4 cPR’s with a median duration of response of 256 days, with responses emerging after 2 cycles of therapy. Responses were observed with CFI-402257 as a single agent and in combination with fulvestrant. Based on these data, study TWT-203 will focus on advanced solid tumors and advanced HR+/HER2- breast cancers in combination with an approved endocrine therapy. Methods: Safety and clinical activity of CFI-402257 monotherapy will be evaluated in patients with advanced solid tumors (Part A) or in combination with fulvestrant in patients with HR+/HER2- advanced breast cancer (Part B). Part A will confirm the RP2D using a 3+3 design with a starting dose of 126 mg daily. Part B evaluates CFI-402257 in combination with fulvestrant in patients with HR+/HER2- advanced breast cancer following progression on prior CDK4/6i and endocrine therapy. Initially 6 patients will be treated with CFI-402257 and fulvestrant, and safety, tolerability, and PK evaluated, with further expansion to confirm the RP2D and characterize CFI-402257 activity. Efficacy endpoints include overall response rate and disease control rate. Safety endpoints include incidence of treatment emergent adverse events. Exploratory objectives include characterization of protein and molecular alterations relevant to the cell cycle and CFI-402257 response.
Identification of the (cancer) extracellular vesicle surface proteome and its application to detect prostate cancer in urine
Authors: I. Bijnsdorp, L.A. Erozenci, F. Feenstra, S.R. Piersma, T.V. Pham, S. Bach, R.D.M Steenbergen, J. Wortel, J.R.T. Van Weering, G. Jenster, C.R. Jimenez
Journal: European Urology (2022)
Exploring the accuracy of multiparametric MRI in prostate cancer staging: An institutional retrospective study.
Authors: Andrew Denisenko, Vasil Mico, Connor McPartland, Cassra B Clark, Andrew Shumaker, Patrick H. Gomella, Joseph Izes, Mark Jonathan Mann, Edouard John Trabulsi, James Ryan Mark, Costas D. Lallas, Leonard G. Gomella, Thenappan Chandrasekar
Journal: Journal of Clinical Oncology (2022)

e17056 Background: Multiparametric Magnetic Resonance Imaging (mpMRI) has been increasingly utilized in prostate cancer (PCa) diagnosis and staging. While there is Level 1 data supporting MRI utility in identifying clinically significant PCa and guiding PCa diagnosis, there is little data on its ability to predict surgical outcomes and its utility as a staging study. We aimed to evaluate the accuracy of mpMRI in predicting common surgical pathology outcomes in patients who underwent radical prostatectomy (RP). Methods: Men who underwent either open radical prostatectomy (ORP) or robotic assisted laparoscopic prostatectomy (RALP) for prostate adenocarcinoma from January-December 2021 at a single tertiary level care academic medical center were identified. Chart review for relevant patient demographics, mpMRI related variables and final surgical pathology was completed. In patients who had pre-operative mpMRI, we evaluated the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of mpMRI in predicting relevant surgical outcomes, including presence of pT2N0 organ confined disease (OCD), extracapsular extension (ECE), seminal vesicle invasion (SVI), lymph node involvement (LNI), and bladder neck invasion (BNI). Results: 168 eligible patients were identified in a 12-month period. The mean age was 63.5±6.24 years and mean Prostate Specific Antigen (PSA) was 11.4±23.7, with 166 (98.8%) patients undergoing RALP and 115 (68.5%) having pre-operative mpMRI. Median GGG was 2 in both MRI and CT subsets (p = 0.580), and patients who had pre-op MRI were more likely to have higher PSA (12.7 ±28.1 vs 8.38± 6.32, p = 0.073) and clinically node positive disease (p &lt; 0.001) than those with CT. However, there was no significant difference in final surgical pathology or positive surgical margin rates between these two groups. On subset analysis of the MRI subset, Table summarizes the sensitivity, specificity, PPV, and NPV of pre-op MRI to predict OCD, ECE, SVI, LNI, and BNI. While specificity of pre-op MRI was adequate for all outcomes (89.1-100%), sensitivity (2.9-49.2%), PPV (40-100%), and NPV (56.3-94.3%) were poor. Conclusions: At present, pre-op MRI of the prostate does not appear to be accurate in its ability to predict important pathologic outcomes at the time of radical prostatectomy and should be used cautiously as a local staging tool. More work is needed before MRI can be used as a reliable staging tool for PCa.[Table: see text]
Bladder Cancer risk in children and adolescents with rare disorders: Experience from Costello syndrome.
Authors: N. Foschi, C. Leoni, P. Russo, S. Silvaroli, F. Pierconti, M. Tartaglia, V. Paradiso, M. Ragonese, F. Fantasia, G.B. Filomena, L. Nanni, G. Zampino, P.F. Bassi
Journal: European Urology (2022)
OTHR-12. Incidentalomas; should benign, indeterminate MRI findings be discussed at the paediatric neuro-oncology MDT
Authors: Alexandra Large, Sue Picton
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: In 2020, 503 patients were discussed at the weekly neuro-oncology MDT meeting, at a UK tertiary paediatric hospital. This was a 50% increase from 2016. Anecdotally, an increased number of non-tumours were being discussed. OBJECTIVES: To determine whether Paediatric Neuro-oncology MDT is consistent with follow up of benign, incidental findings on MRI scan and whether these lesions become significant.METHODS: MDT discussion notes reviewed for all incidental and benign MRI head findings between 05/09/18 and 02/09/20.RESULTS: 59 MRI head lesions, that were deemed to be both incidental and benign were discussed at the MDT. 44% of referrals were from the local hospital; this may be due to availability of the MDT or complexity of the patient cohort. Findings discussed included pineal cysts (24), arachnoid cysts (3), epidermoid cysts (1), pituitary lesions (4) and other indeterminate lesions or signal change (27). The majority of children received serial MRI imaging after MDT. There were large inconsistencies in the follow-up interval recommended, even within similar pathologies. For example, pineal cysts follow up ranged from no repeat imaging to multiple repeat scans with 6 and 12 month intervals. ‘Complex’ cysts were more likely to receive follow up but there is little consensus between radiologists about criteria for a ‘complex cyst’. None of the lesions reviewed changed significantly over time. Perhaps most strikingly, only 2/27 of the ‘indeterminate lesions’ have been discharged from the MDT. CONCLUSIONS: As clinical reasoning is seldom recorded in reports or MDT discussion notes the reasons for different surveillance recommendations is difficult to ascertain retrospectively. However, as MRI scans become more readily available incidental and being findings will increase, potentially putting great pressure on an already stretched service. Serial MRI imaging also creates unnecessary anxiety for both the child and their family.
Feasibility of radio-guided lymph node dissection in primary oligometastatic prostate cancer patients: An interim analysis
Authors: M.G.M. Schilham, R. Hermsen, H.V.N. Küsters Vandevelde, H.J.E.J. Vrijhof, R.J. Hoekstra, J-P.A. Van Basten, M. Gotthardt, D.M. Somford, J.P.M. Sedelaar, M. Rijpkema
Journal: European Urology (2022)
Prospective randomized comparison of SP TFL and Ho:YAG in RIRS for kidney stones: a single-center study
Authors: C. Azilgareeva, M. Taratkin, V. Petov, D. Korolev, G. Akopyan, A. Dymov, D. Chinenov, S. Ali, O. Traxer, D. Enikeev
Journal: European Urology (2022)
A prospective multicenter comparison study of a risk-adapted ultrasound-directed and MRI-directed diagnostic pathway in prostate cancer suspected biopsy naïve men
Authors: I.M. Wagensveld, D.F. Osses, P.M. Groenendijk, F.M. Zijta, M.B. Busstra, E. Rociu, J.O. Barentsz, J.P.M Sedelaar, B. Arbeel, T. Roeleveld, R. Geenen, I. Koeter, S.A. Van Der Meer, V. Cappendijk, R. Somford, S. Klaver, H. Van Der Lely, T. Wolters, W. Hellings, M.R. Leter, H.G. Van Der Poel, S.W.T.P.J. Heijmink, F. Debruyne, J. Immerzeel, I.G. Schoots
Journal: European Urology (2022)
INSP-14. Novel approaches to molecular diagnostics
Authors: Felix Sahm
Journal: Neuro-Oncology (2022)

Abstract The 2021 WHO classification of brain tumors introduces a variety of novel tumor types and subtypes, especially in pediatric neuro-oncology. Most of these tumor types are characterized by specific molecular profiles and alterations. In turn, diagnostic molecular evaluation of brain tumor specimen becomes substantially more complex. The talk will review the basic concepts of the new WHO classification and present novel methodology developments with the respective implications in diagnostic routine. This covers, first, RNA sequencing for fusion detection and expression profiling, highlighting examples of novel tumor types identified by pathognomonic rearrangements. Second, long-read sequencing approaches selecting DNA fragments of interest during sequencing will be discussed. Third, an outlook on the use of artificial intelligence to classify and detect molecular alterations based on H&amp;E staning alone will be provided.
Neoadjuvant dabrafenib and trametinib (D+T) for stage III melanoma: Long-term results from the NeoCombi trial.
Authors: Alexander M. Menzies, Robyn P.M. Saw, Serigne N. Lo, Maria Gonzalez, Sydney Ch'ng, Omgo E. Nieweg, Kerwin Frank Shannon, Peter M. Ferguson, Jenny HJ Lee, Helen Rizos, Robert V Rawson, Jonathan Stretch, John F. Thompson, Louise Emmett, Rony Kapoor, Andrew John Spillane, Richard A. Scolyer, Georgina V. Long
Journal: Journal of Clinical Oncology (2022)

9580 Background: Neoadjuvant D+T has a high pathologic response rate and impressive short-term survival. The NeoCombi trial (NCT01972347) enrolled 35 patients with resectable stage III melanoma, with last patient commencing treatment April 19th 2017. We report 5-year outcomes from this trial. Methods: Pts received 12 wks neoadjuvant standard dose D+T, then 40 wks adjuvant D+T. Eligible pts were ≥ 18 yrs, ECOG PS ≤ 1 with clinical stage III BRAF V600E/K melanoma. CT and PET scans were performed at baseline and prior to surgery. Pathologic response was determined as per International Neoadjuvant Melanoma Consortium (INMC) criteria and defined as complete (pCR), near complete, partial (pPR) or no response (pNR). CT monitoring was continued 12 wkly thereafter to 2 yrs, then 6 monthly to 3 yrs, then as standard care. The primary endpoints were the complete pathological response (pCR) and RECIST response rate (rRR) at wk 12. Secondary endpoints included relapse free survival (RFS), OS, and toxicity. Results: 35 pts were enrolled, 6 with IIIB, 29 IIIC (7 ITM only) disease (clinical AJCCv7). At data cut August 17th 2021, median F/U was 60 mo (95% CI 56-72). No patients progressed in the neoadjuvant phase, and (49%) had a pCR, 1 near pCR, 6 pPR, 11 pNR. 5-year RFS, DMFS and OS data are shown in the Table. The majority of recurrences occurred within the first 2 years, with no recurrences beyond 3y. 21 patients recurred; 12 (57%) had first recurrence locoregional (6/12 subsequent distant recurrence) and 9 (43%) had first recurrence in distant sites (3/9 in brain). Locoregional recurrence was managed with surgery alone in 4/12, systemic therapy alone in 2/12, or both surgery and systemic therapy in 5/12 (4/5 had adjuvant systemic therapy), 1 pt was observed until distant recurrence. Subsequent systemic therapy in the 15 patients with a distant recurrence included PD-1 based immunotherapy (N=14) and BRAF targeted therapy (N=10). Conclusions: Neoadjuvant D+T in clinical stage III melanoma has impressive early activity, however patients remain at high risk of recurrence. Pathologic response can identify patients at the highest risk of recurrence, offering a chance of alternative adjuvant therapy in non-responders. Clinical trial information: NCT01972347. [Table: see text]
Gemcitabine plus cisplatin versus non-gemcitabine and cisplatin regimens as neoadjuvant treatment for cholangiocarcinoma patients prior to liver transplantation.
Authors: Maen Abdelrahim, Abdullah Esmail, Jiaqiong Xu, Godsfavour Umoru, Ashish Saharia, Robert McMillan, Rafik Mark Ghobrial
Journal: Journal of Clinical Oncology (2022)

e16202 Background: Cholangiocarcinoma (CCA)management is constantly being updated in view of existing evidence in order to establish practice guidelines and consensus statements. Here, we evaluate and compare the potential efficacy of chemotherapy combination of Gemcitabine plus Cisplatin versus non- Gemcitabine and Cisplatin regimens as a neo-adjuvant treatment for cholangiocarcinoma patients prior to liver transplantation. Methods: In this prospective study, patients with locally advanced, unresectable, hilar, or intrahepatic CCA with no evidence of extrahepatic disease or vascular involvement were treated with either the combination of neo-adjuvant Gemcitabine plus Cisplatin with no radiation or other standard options of neo-adjuvant treatment. All patients included received chemotherapy prior to being listed for liver transplantation at a single cancer center in collaboration with the same institution’s transplant center according to an open-labeled, and centers-approved clinical management protocol. Patients were listed for liver transplantation if they had a minimum of six months of scans showing response or confirmation of disease stability. This report, which was censored on November 30, 2021, was an initial prospective study of patients treated under this ongoing clinical treatment protocol. Results: Out of a total of 707 liver transplant recipients, 37 patients were confirmed with a diagnosis of CCA and only 18 patients (11 males and 7 females) with a median age of 61.83 [interquartile range (IQR): 58.27-68.74] met inclusion criteria. Of the 18 patients enrolled, 10 received Gemcitabine/Cisplatin, while 8 patients received either Gemcitabine monotherapy or Capecitabine or FOLFIRI alone or with Cetuximab. Days for recurrence after transplantation was 603 (IRQ: 603-603) in the Gemcitabine/Cisplatin group and 285 (267-374) days in the non-Gemcitabine/ Cisplatin group (p-value = 0.18). The median days of follow-up in the Gemcitabine/Cisplatin group were 753 (621-885) days versus 1050 (618-1489) days in the non-Gemcitabine/ Cisplatin group (p-value = 0.25). In the non-Gemcitabine/ Cisplatin group, overall survival was 75% (95% CI 31-93%) at both years 1 and 2; 63% (95% CI 23-86%) at both years 3 and 4. In the Gemcitabine/ Cisplatin group, overall survival was 100% (95% CI 100-100%) at both years 1 and 2; 67% (95% CI 5-95%) at both years 3 and 4. Three patients in the non-Gemcitabine/ Cisplatin group died at 328 days, 340 days, and 896 days, respectively. One patient in the Gemcitabine/ Cisplatin group died at 885 days. Conclusions: To our knowledge, this is the first report to show improved overall survival outcomes with Gemcitabine plus Cisplatin as neo-adjuvant treatment with no concomitant radiation compared to non-Gemcitabine/ Cisplatin regimens in patients with CCA prior to liver transplantation.
Analysis of the effect of systemic corticosteroids on survival from tebentafusp in a phase 3 trial of metastatic uveal melanoma.
Authors: Alexandra Ikeguchi, Joseph J. Sacco, Jason J. Luke, T.R. Jeffry Evans, Brendan D. Curti, Kevin B. Kim, Shaad Essa Abdullah, Claire Watkins, Ozgur Karakuzu, Paul D. Nathan
Journal: Journal of Clinical Oncology (2022)

9584 Background: All immune therapies that rapidly activate T cells, including T cell engagers, can induce cytokine release syndrome (CRS). Tebentafusp (tebe), a T cell receptor bispecific (gp100 x CD3) can also induce skin adverse events (AEs), due to gp100+ cutaneous melanocytes. CRS and skin AEs may require management with short term corticosteroids, which may also be used as premedication for subsequent tebe doses. Here we report the first analysis of systemic corticosteroid use and correlation with efficacy from a Phase (Ph) 3 trial for any T cell engager. Methods: Post hoc analyses were performed on the tebe arm of the Ph3 [NCT03070392] study in previously untreated HLA-A*02:01+ metastatic uveal melanoma (mUM) (N = 245). Due to the low rate of severe AEs in Ph1 trials, prophylactic corticosteroids were not mandated. The association between overall survival (OS) and corticosteroid use (new start within 30 days of first tebe dose) was investigated using landmark analyses in the safety population. Multivariate analyses were adjusted for key patient characteristics and AEs of special interest: CRS, rash, and liver function test (LFT) elevation. Steroid type (hydrocortisone vs. others) and treatment duration (1 vs. &gt; 1 day) were also investigated. Results: In the Ph3 trial, 64/245 (26%) patients received new systemic corticosteroid within 30 days after the first dose of tebe, mostly for treatment of AEs (56/64, 88%) or pre-medication due to previous AE (14/64, 22%). 25 of the 64 patients received corticosteroids only for a single day. The most frequent AEs (≥15%) were rash (18/64, 28%), CRS (15/64, 23%), and hypotension (12/64, 19%). In a logistic regression model, elevated baseline LDH, the dominant prognostic marker, was most strongly associated with use of corticosteroids (p = 0.01). In the multivariate analysis, corticosteroids were not associated with any significant OS difference (HR 1.41, 95% CI 0.83-2.4, p = 0.2) and this effect did not differ in patients with or without CRS, rash or LFT elevation (all interaction tests p &gt; 0.2). There was no difference in OS according to corticosteroid type or whether administered for 1 vs &gt; 1 day. Conclusions: This is the first analysis from a phase 3 trial of the impact of systemic corticosteroids on survival for a T cell engaging cancer therapy. The vast majority of tebe-treated patients (84%) either did not require corticosteroids (74%) or only received them on a single day (10%). The most frequent reason for corticosteroid use was an emergent AE, including CRS and rash. Corticosteroid use following the pre-specified AE guidelines was not associated with any significant impact on OS. Clinical trial information: NCT03070392.